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WO2011095997A1 - Composés de benzamide à titre d'activateurs de glucokinase et leur application pharmaceutique - Google Patents

Composés de benzamide à titre d'activateurs de glucokinase et leur application pharmaceutique Download PDF

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Publication number
WO2011095997A1
WO2011095997A1 PCT/IN2011/000086 IN2011000086W WO2011095997A1 WO 2011095997 A1 WO2011095997 A1 WO 2011095997A1 IN 2011000086 W IN2011000086 W IN 2011000086W WO 2011095997 A1 WO2011095997 A1 WO 2011095997A1
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pyridin
yloxy
cyclopropanesulfonyl
isopropoxy
alkyl
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PCT/IN2011/000086
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English (en)
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Anil Deshpande
Sachin Kandalkar
Keshav Naik
Bhavesh Dave
Debnath Bhuniya
Venkata Palle
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Advinus Therapeutics Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This disclosure relates to a series of benzamide compounds, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof.
  • the disclosure also relates to process of preparation of the benzamide compounds.
  • the compounds of the present disclosure are identified as Glucokinase activators or modulators, which are beneficial for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, such as diabetes, metabolic syndrome, and/or diabetes-related complications including retinopathy, nephropathy, neuropathy, ischemic heart disease, arteriosclerosis, ⁇ -cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
  • Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition.
  • Glucose level abnormalities can result in serious long-term complications, which include beta-cell dysfunction, glucotoxicity, cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage, macrovascular damage, adipocyte inflammation, vascular inflamation and obesity.
  • Glucokinase also known as hexokinase IV or D, is one of four glucose- phosphorylating enzymes called hexokinases that catalyze the first step of glycolysis, the conversion of glucose to glucose 6-phosphate (G6P), in vertebrate tissues.
  • GK functions in a dual role, with distinct functions in the pancreas and liver; (a) as a molecular glucose sensor in the insulin-producing pancreatic ⁇ -cells, and (b) as the high-capacity enzymatic step initiating the storage of glucose in the form of glycogen in the liver and uptake of glucose during hyperglycemia.
  • GK plays a central role in glucose homeostasis, through the phosphorylation of glucose in the liver, and the modulation of insulin secretion in the pancreas (Postic, C. et al (1999) J. Biol. Chem. 274: 305-315). GK also functions as a sensor in other neuroendocrine cells of the gastrointestinal tract and in various brain cells including specific cells in the hypothalamus (Jetton, T. A. et al (1994) J. Biol. Chem. 269: 3641 -3654).
  • the physiological concentration of glucose in human plasma is approximately 5.5 mM under fasting conditions, and increases to about 12 mM in the fed state. This concentration is dependent on and maintained by the activity of GK, which senses glucose and controls metabolic flux in key cell types.
  • the glucose concentration, at which GK activity is at half of its maximal velocity or V m a Xj is defined as its S0.5.
  • the S0.5 of GK for glucose lies in the middle of the physiological glucose concentration range at approximately 8 mM, allowing this enzyme to act as a molecular glucose sensor crucial for glucose homeostasis.
  • the limited tissue distribution and unique kinetic properties of GK allow it to play a critical role in pancreatic ⁇ -cell insulin secretion and hepatic glucose utilization.
  • GK differs from the other members of the mammalian hexokinase family in its unique sigmoidal kinetics with respect to glucose, a high S0.5 that lies in the physiological glucose concentration range (the other three mammalian hexokinases have S0.5 values less than 0.5 mM), the lack of product inhibition by G6P, and its tissue distribution in cell types that are thought to be responsive to changing plasma glucose levels.
  • GK mutations have a profound influence on glucose homeostasis.
  • About 2000 GK mutations that have been identified in humans result in impaired glucose-mediated insulin secretion and maturity-onset diabetes of the young type 2 (MODY-2).
  • MODY-2 impaired glucose-mediated insulin secretion and maturity-onset diabetes of the young type 2
  • Some of these mutations result in decreased accumulation of hepatic glycogen, while others decrease GK activity by reducing the stability of the enzyme or by decreasing its V max .
  • Mutations that result in activation of GK are implicated in the onset of persistent hyperinsulinemic hypoglycemia of infancy (PHI-ll).
  • Single point mutations e.g.
  • GK activity can be regulated through allosteric modulation.
  • GKAs small-molecule glucokinase activators
  • WO 2007/031739, WO 2006/125958 discloses phenyl substituted heterocyclic compounds that are glucokinase activators or modulators.
  • WO 2007/007041, WO 2008/154563, US 2009/0018Q56, WO 2009/041475 and WO 2009/046802 describe benzamide derivatives as glucokinase activators.
  • the present disclosure provides a novel class of benzamide compounds characterized as glucokinase activators or modulators, and their potential use as medicament for the prophylactic or therapeutic treatment of hyperglycemia, diabetes, obesity, dyslipidemia, metabolic syndrome and like.
  • the present disclosure relates to a series of benzamide compounds described by formula (1), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof;
  • ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1- 4 hetero atoms independently selected from N, O, or S with at least one nitrogen in the ring;
  • X is selected from O or a bond;
  • ring-C is selected from an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heteroaryl;
  • R 1 is selected from an unsubstituted or a substituted alkyl, an unsubstituted or a substituted alkenyl, an unsubstituted or a substituted alkynyl, an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted cycloalkylalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted arylalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heterocyclylalkyl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heteroarylalkyl;
  • R' and R° are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl, and perfluoroalkyl, or
  • R 3 and R 4 ring-B can be further optionally substituted with one or more substituents independently selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR 5 , -C(0)NR 5 R 6 , -OR 5 , -SR 5 or -NR 5 R 6 ;
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1 , 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • substituted alkyl refers to: 1) an alkyl group or alkylene group as defined above, having 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino,
  • substituents may optionally be further substituted by 1, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2; or 2) an alkyl group or alkylene group as defined above that is interrupted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms independently selected from oxygen, sulfur and NR d , where R d is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, carbonylalkyl, carboxyester, carboxyamide or sulfonyl.
  • substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or - S(0) p R c , in which R c is alkyl, aryl, or heteroaryl and p is 0, 1 , or 2;
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • alkynylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon grSup preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • cycloalkyl refers to unless otherwise mentioned, carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings which may be saturated or partially unsaturated.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, l,3,3-trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3- trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -C(0)R and -S(0) p R b , where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxywhere R b is alkyl, aryl
  • substituents may optionally be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(0) p R c where R c is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Haloalkyl refers to a straight chain or branched chain haloalkyl group with 1 to 6 carbon atoms.
  • the alkyl group may be partly or totally halogenated.
  • Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2- fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.
  • alkoxy refers to the group R"'-0-, where R'" is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.
  • acyloxy refers to the groups -OC(0)-alkyl, -OC(0)-cycloalkyl, -OC(0)-aryl, - OC(0)-heteroaryl, and -OC(0)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or - S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Di alkylamino refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with 1 to 6 carbon atoms are bound.
  • Representative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the invention are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.
  • ring-B is selected from imidazole, oxazole, pyridine, pyrazole, pyrazine, pyrimidine, thiazole, thiazolone, thiazolopyridine, thiazolopyrimidine, benzothiazole, benzopyrimidine, thiadiazole, thiazolopyrimidine, thiazolopyridine, quinoline, isoquinoline, tetrahydrobenzothiazole, tetrahydrothiazolopyridine, tetrahydrothiazolopyrimidine, tetrahydroquinoline or tetrahydroisoquinoline;
  • R 5 and R 6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S,
  • Another embodiment of the present invention further provides compound of formula I , or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, wherein
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl and perfluoroalkyl;
  • Another embodiment provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for preventing diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
  • Further embodiment of the invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for combined treatment or prevention of diabetes and obesity. In yet another embodiment it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating or preventing obesity.
  • Another embodiment of the present invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treatment or prevention of dyslipidemia.
  • the present invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating hyperglycemia, IGT, Syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia hypertension, for the treatment or prophylaxis of obesity, for lowering of food intake, for appetite regulation, or for regulating feeding behaviour.
  • it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for enhancing the secretion of enteroincretins, like GLP-1 and GIP, thereby managing diseases or disorders associated with modulation of secretions of enteroincretins, like hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts.
  • enteroincretins like GLP-1 and GIP
  • diseases or disorders associated with modulation of secretions of enteroincretins like hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataract
  • An embodiment of the present invention also provides use of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the activation of Glucokinase.
  • Further embodiment provides a method of combined treatment or prevention of diabetes, obesity and dislipidemia by administering an effective amount of a compound of formula (I) of the present invention, its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
  • GKAs glucokinase activators
  • Compounds of formula I may be prepared as shown in the following reaction schemes and the description thereof, as well as relevant literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and deprotection in the schemes below may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]).
  • the present disclosure relates to a process for the preparation of a compound of formula (I), its stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, polymorph, or solvates.
  • Methyl 3,4-dihydroxy benzoate (VII) may be reacted with halide R'-Hal under substitution reaction condition to obtain mono O-derivatized product of formula (VIII).
  • Another O- deriyatization of VIII under substitution reaction condition using compound of formula V followed by hydrolysis of ester IX under basic condition provides acid II.
  • ALK alkylene C 3.6
  • the amide coupling reaction may be carried out in the presence of solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitrile or mixture of them may be used at a temperature ranging from -5 to 150 °C.
  • the reaction may be carried out optionally in presence of catalytic amount of DMF.
  • Condition-II When R is not H, the amide coupling may be carried out by heating ester and amine either in the absence of solvent or in presence of high boiling solvent like toluene, xylene, DMSO. Amide coupling may be carried out in presence of trialkyl aluminium (Chem. Commun., 2008, 1 100-1 102).
  • Substitution reaction may be carried out using any suitable organic or inorganic bases.
  • Organic bases may be selected from a group consisting of mono, di or trialkyl amines particularly methylamine, ethylamine, dimethylamine, diethylamine or triethylamine.
  • Inorganic bases may be selected from a group consisting of alkali and alkaline earth metal hydrides, hyroxides, carbonates and bicarbonates or mixtures thereof.
  • Solvents used for this reaction may be selected from a group consisting of lower alcohols, acetone, acetonitrile, DMSO, DMF, dimethylacetamide, THF and toluene, or mixtures thereof.
  • This reaction may be carried out using strong nonnucleophilic base such as potassium -ter/-butoxide, Lithium diisopropylamide to generate a carbanion at a-carbon of sulfone group.
  • strong nonnucleophilic base such as potassium -ter/-butoxide, Lithium diisopropylamide to generate a carbanion at a-carbon of sulfone group.
  • anionic nucleophile would lead to intramolecular substitution to form the ring-C.
  • Ester hydrolysis of carboxylic acids may be carried out using general saponification conditions employing inorganic bases such as alkali and alkaline earth metal hyroxides, carbonates and bicarbonates, for example lithium hydroxide, sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like; in the presence of solvents such as water, methanol, ethanol, THF and diethyl ether or mixtures thereof. These reactions may be done at 0 °C to refluxing temperature.
  • inorganic bases such as alkali and alkaline earth metal hyroxides, carbonates and bicarbonates, for example lithium hydroxide, sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • solvents such as water, methanol, ethanol, THF and diethyl ether or mixtures thereof.
  • any reactive group present such as hydroxyl, amino, carbonyl, imino and the like, may be protected during the reaction by conventional protecting groups such as trimethylsilyl, ter-butyl methyl silyl, benzyl, acetal, ketal and the like, which are cleaved again after the reaction.
  • the compounds of formula (I) may be prepared by derivatisation of formula (I) by transformations well known to those skilled in the art, e.g functional groups as R 3 or R 4 may be transformed to different functional groups such as an ester function being converted to an acid, amide, hydroxyalkyl, keto, aldehyde as well as an ester.
  • the said conversions may be carried out using reagents and conditions well documented in the literature.
  • any of the compounds of formula (I) may be converted into a pharmaceutically acceptable salt or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
  • salts of compounds of formula (I) covers salts of compounds of formula (I) prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Inorganic bases salts include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene- diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • therapeutically effective amount in this disclosure, it means an amount of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, that is sufficient for effective treatment of obesity and/or type II diabetes.
  • the therapeutically effective amount or dosage of a compound according to this disclosure can vary within wide limits. The dosage will depend on individual requirements in each particular case including the specific compound(s) being administered, the manner of administration, the severity of condition being treated, as well as the patient being treated, which is readily determinable by a person skilled in the art.
  • a daily dose in the range for example, about 0.01 mg to 100 mg per kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, about 0.01. mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, about 0.01 mg to 30 mg per kg body weight will be used.
  • the compounds and compositions of the present disclosure may be optionally employed in combination with one or more, from current or future therapy, other antidiabetic agents or anti-hyperglycemic agents, which include, for example, (a) insulin secretagogues such as sulfonylureas (e.g. Amaryl, glyburide, glimepiride, glipyride, glipizide, etc.); (b) Insulinotropic sulfonyl urea receptor ligands such as meglitinides (e.g. nateglinide, rapaglinide); (c) biguanides (e.g. metformin etc.); (d) glucagon antagonists (e.g.
  • glucosidase inhibitors e.g. acarbose, miglitol, etc.
  • glucose sensitive insulinotropic agents e.g. GLP-1 , GLP-1 mimetics e.g Exendin-4; GLP-1, GPR-1 19, GPR-40, GPR120 and like other receptor modulators chosen from small molecule or from peptides
  • insulin sensitizers e.g. rosiglitazone, pioglitazone, balaglitazone etc.
  • Dipeptidyl peptidase-IV inhibitors e.g.
  • dyslipidemic agents which include, for example: (a) fibrates (e.g. gemfibrozil, fenofibrate); (b) Niacin; (c) Statins (e.g. rosuvatatin, atorvastatin, simvastatin); (d) cholesterol absorption inhibitors (e.g. Ezetimibe); (e) bile acid sequestrants (e.g. cholestyramine) and the like.
  • fibrates e.g. gemfibrozil, fenofibrate
  • Niacin e.g. rosuvatatin, atorvastatin, simvastatin
  • Statins e.g. rosuvatatin, atorvastatin, simvastatin
  • cholesterol absorption inhibitors e.g. Ezetimibe
  • bile acid sequestrants e.g. cholestyramine
  • antihypertensive agents such as: (a) diuretics (e.g hydrochlorothiazides, mannitol, indapamide, furosemide); (b) angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril); (c) Angiotensin-II receptor type-I blockers (ARB) (e.g. losartan, irbesartan); (d) rennin inhibitors (e.g aliskerin); (e) ⁇ -adrenergic receptor blockers (e.g.
  • diuretics e.g hydrochlorothiazides, mannitol, indapamide, furosemide
  • ACE angiotensin converting enzyme
  • ARB Angiotensin-II receptor type-I blockers
  • rennin inhibitors e.g aliskerin
  • ⁇ -adrenergic receptor blockers e.g.
  • the disclosure also relates to pharmaceutical composition
  • pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, wherein the pharmaceutically acceptable therapeutically active agent is selected from anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents or anti-dyslipidemic agents.
  • compositions containing the active ingredient of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof maybe in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs; sterile injectable aqueous or oleaginous suspension; suppositories; topical use, for example creams, ointments, jellies, solutions or suspension etc including mouth washes and gargles.
  • These compositions can be manufactured by any method known in the art with the active ingredient combined with non-toxic pharmaceutically acceptable excipients.
  • HBTU 0-(benzotriazol-l-yl)-tetramethyluronium hexafluorophosphate
  • HATU 0-(7-azabenzotriazol-l-yl)-tetramethyluronium hexafluorophosphate
  • PTSA jcora-toluene sulfonic acid
  • DIAD diisopropyl azodicarboxylate
  • diastereomeric or enantiomeric products When diastereomeric or enantiomeric products are obtained as mixtures, they can be separated by conventional methods for example, chromatographic separation or fractional crystallization or through diasteriomeric salt formation. When intended, a desired enantiomer or diasteriomer can also be obtained by following appropriate enantioselective or diastereoselective reactions.
  • reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 X 150mL); this solution was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography (silica gel 100-200 mesh, 20% ethylacetate in hexanes as eluent) to provide the Product (4.2 g).
  • StepII 3-(6-CycIopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid methyl ester :
  • StepIII 3-(6-Cyclopropanesulfonyl-pyridin-3-yIoxy)-5-isopropoxy-benzoic acid : To a stirred solution of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid methyl ester (2.48 g, 6.34 mmol) in tetrahydrofuran, methanol & water (3: 1 : 1, 50 mL) was added NaOH (0.76 g, 19.02 mmol) at room temperature and stirred for 8 h. After completion of reaction, organic solvent was removed under reduced pressure.
  • Step-V - Synthesis of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l- methyl-ethoxy)-benzoic acid
  • Step-I 3-Benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester:
  • Step-II - 3-Benzyloxy-5-isobutyl-benzoic acid methyl ester :
  • Step IV 3-(6-CycIopropanesuIfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid methyl ester :
  • Step V 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid
  • the aqueous layer was neutralized to pH ⁇ 7 using IN HC1 and was extracted with ethyl acetate (3 X 20 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the desired product (0.35 g).
  • Step I 4-(5-Nitro-pyridin-2-yloxy)-benzoic acid methyl ester
  • Step I Synthesis of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester: A mixture of (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (5g, 26.85 mmol) and da-tert- butoxydicarbonate (8.2g, 37.59 mmol) was heated at 80 °C in toluene for 24 hrs. Toluene was removed under vacuo and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the oily product (7.5
  • Step II Synthesis of ⁇ 2-[tert-ButoxycarbonyI-(4-methoxy-benzyl)-amino]-thiazol-4-yI ⁇ - acetic acid ethyl ester :
  • the reaction was done by the same way as mentioned in the step III.
  • the crude product was purified by column chromatography (Silica gel 60 -120 mesh, and 2-4% ethyl acetate in hexanes as eluent) to get the pure solid compound (58.51%). .
  • Step VI Synthesis of 2-(2-Amino-5-chloro-thiazol-4-yl)-2-methyl-propionic acid ethyl ester:
  • Step I 2- ⁇ 2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-5-fluoro-thiazoI-4-yl ⁇ -2- methyl-propionic acid ethyl
  • Step II 2-(2-Amino-5-fluoro-thiazol-4-yI)-2-methyl-propionic acid ethyl ester
  • reaction mixture was diluted with DCM (5 mL) & kept in an ice bath at °C followed by slow addition of 2-amino-5-fluoro-thiazole.HCL (74 mg, 0.48 mmol) in DMF (5 mL) & triethyl amine (0.138 ml, 1 mmol) in DCM (2 mL). After the addition was over the reaction mixture was continued to stirr for 4 h. at room temperature. The reaction mixture was diluted with DCM and neutralized to pH ⁇ 7 using IN aqueous HC1. The organic layer was separated; washed with wa ' ter, followed by brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude compound which was purified by preparative TLC or column chromatography to provide the final compound Al (60 mg).
  • the glucokinase (GK) assay is a coupled enzymatic assay.
  • GK catalyzes the first step of glycolysis, the conversion of glucose to glucose-6-phosphate (G6P) in the presence of ATP.
  • G6P in turn is converted by glucose-6-phosphate dehydrogenase (G6PD) to 6- phosphogluconate, a process that requires NAD, resulting in NADH formation. Since the GK-catalyzed step is the rate-limiting step of this coupled enzymatic process, the rate of accumulation of 6-phosphogluconate and NADH is directly proportional to the rate of glucose phosphorylation by GK.
  • the rate of the GK-catalyzed reaction can therefore be measured by monitoring the increase in NADH absorbance at 340 nm.
  • the assay is carried out according to the protocol outlined in Hariharan et al (1997), Diabetes 46: 1 1 -16. Briefly, the test compounds are incubated in a reaction mix containing 25 mM HEPES (pH 7.2), 10 mM MgCl 2 , 100 mM KC1, 5 mM ATP, 2 mM DTT, 0.5 mM NAD, 1 U/ml Leuconostoc mesenteroides G6PD, 0.3 U/ml of purified human recombinant GK, and different concentrations of glucose. Enzymatic activity is calculated from the initial reaction velocity, measured from the change in NADH absorbance as a function of time.
  • a compound is considered to be a giucokinase activator if it, in its testable range of concentrations, yields a higher rate of glucose phosphorylation than in its absence at a particular glucose concentration, for example at 5 mM glucose.

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Abstract

Composés de benzamide de formule (I), leurs stéréoisomères, tautomères, pro-médicaments, sels pharmaceutiquement acceptables, polymorphes, solvates, et formulations, utiles à titre d'activateurs ou de modulateurs de glucokinase. Un procédé de préparation desdits composés de benzamide est également décrit.
PCT/IN2011/000086 2010-02-08 2011-02-07 Composés de benzamide à titre d'activateurs de glucokinase et leur application pharmaceutique WO2011095997A1 (fr)

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WO2016112863A1 (fr) * 2015-01-14 2016-07-21 中国科学院上海药物研究所 Composé benzamide n-substitué-3,5-disubstitué et ses procédé de préparation et application
CN117043147A (zh) * 2020-12-17 2023-11-10 纳鲁生物股份有限公司 大麻二酚及其类似物的合成以及相关化合物、制剂和使用方法

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WO2016112863A1 (fr) * 2015-01-14 2016-07-21 中国科学院上海药物研究所 Composé benzamide n-substitué-3,5-disubstitué et ses procédé de préparation et application
CN105837599A (zh) * 2015-01-14 2016-08-10 中国科学院上海药物研究所 N-取代-3,5-二取代苯甲酰胺类化合物及其制备方法和应用
CN107108656A (zh) * 2015-01-14 2017-08-29 中国科学院上海药物研究所 N‑取代‑3,5‑二取代苯甲酰胺类化合物及其制备方法和应用
CN107108656B (zh) * 2015-01-14 2019-11-05 中国科学院上海药物研究所 N-取代-3,5-二取代苯甲酰胺类化合物及其制备方法和应用
CN117043147A (zh) * 2020-12-17 2023-11-10 纳鲁生物股份有限公司 大麻二酚及其类似物的合成以及相关化合物、制剂和使用方法

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